Project Summary The goal of the proposed project is to test in macaques a technique for non-invasive, safe, reversible, modulation of neuronal activity in small targeted regions of the primate brain. We have developed and tested in macaques a technique for transiently opening the blood-brain barrier (BBB) in targeted brain regions without causing any damage, using a clinically available focused ultrasound device in conjunction with circulating microbubbles. We now propose to combine this transient BBB opening with the systemic administration of neuroactive substances that normally do not cross the BBB to test whether these substances will have neuroactive effects only in the region with permeabilized BBB. We have tested the BBB permeabilization technique extensively in macaques, and we have tested the technique of combining BBB permeabilization and neuromodulation in rats. The goal of this project is to extend the neuromodulation technique to macaques, to optimize parameters in macaques for clinical applicability, to test this technique in a disease model, and to test in rats both excitatory and suppressive neuromodulation. This technique will be important for basic research, and, more importantly, directly translatable to human patients for neuro-ablation planning.